Extrusion of a polytetrafluoroethylene (PTFE) pilot seal located in the Space Shuttle Orbiter Primary Reaction Control Subsystem (PRCS) thruster fuel valve has been implicated in 68 ground and on-orbit fuel valve failures. A rash of six extrusion-related in-flight anomalies over a six-mission span from December 2001 to October 2002 led to heightened activity at various NASA centers, and the formation of a multidisciplinary team to solve the problem. Empirical and theoretical approaches were used. For example, thermomechanical analysis (TMA) and exposure tests showed that some extrusion is produced by thermal cycling; however, a review of thruster service histories did not reveal a strong link between thermal cycling and extrusion. Calculations showed that the amount of observed extrusion often exceeded the amount allowed by thermally-induced stress relief. Failure analysis of failed hardware also revealed the presence of fuel-oxidizer reaction product (FORP) inside the fuel valve pilot seal cavity, and differential scanning calorimetry (DSC) showed that the FORP was intimately associated with the pilot seal material. Component-level exposure tests showed that FORP of similar composition could be produced by adjacent oxidizer valve leakage in the absence of thruster firing. Specific gravity data showed that extruded fuel valve pilot seals were less dense than new pilot seals or oxidizer valve pilot seals, indicating permanent modification of the PTFE occurred during service. It is concluded that some thermally-induced extrusion is unavoidable; however, oxidizer leakage-induced extrusion is mostly avoidable and can be mitigated. Several engineering level mitigation strategies are discussed.